Using Genetics Toward Solving Kidney Disease

It took Barry Freedman, MD, a generation to help disprove a long-held theory that high blood pressure in African-Americans commonly caused non-diabetic kidney disease.

Now, with widespread acceptance of a genetic link as the cause, Freedman and his colleagues at Wake Forest Baptist Medical Center are facing a new challenge – how to turn their genetic knowledge into a cure for kidney disease.

The numbers show the importance of the work: 26 million American adults suffer from chronic disease of the kidneys, which remove waste products and excess fluid from the body. When 85 to 90 percent of kidney function has been lost, people have what is referred to as end-stage renal disease. They typically receive dialysis, a costly, time-consuming and sometimes painful way of cleansing their system.

Freedman was part of a team of scientists that in 2010 first identified the idea that people with two coding variants in the gene APOL1 are far more likely to develop kidney disease.

Even so, not all people with those two risk variants will develop kidney disease. That means there is a “second hit,’’ as Freedman says, that triggers the disease.

“We know there is a second factor,’’ he says. “If we can find it, I think we can rapidly develop a cure or way to slow progression of this disease.’’

One Family’s Story

Mary Sinclair speaks softly, a whisper almost, discussing her life since she found out her kidneys were failing in 2002. It has been a most difficult 12 years, and yet she is fully aware she is one of the fortunate ones.

After 3½ years of dialysis, she was placed on a transplant list and just a week later got a call that a match had been found. But the kidney from a deceased donor brought complications from the start, and her body rejected it in 2007, putting her right back where she had been, on a debilitating program of dialysis.

Her daughter, LaTasha Siler, knows how tough that was for her mom.

“It was painful for her. After dialysis, all she could do was sleep. She was drained,’’ Siler says. “She used to always be out and doing things. She loved to make flower arrangements. She was very creative. Now she wasn’t able to do those things.”

Siler decided, after months of research and discussions with her father and her husband, to do something about it. She had herself tested and learned she was a donor match to her mother. On Dec. 1, 2011, at Wake Forest Baptist Medical Center, Siler gave her mom her a second transplanted kidney.

More than two years later, mother and daughter are both doing fine.

“The greatest change has been her ability to interact and enjoy time with her grandchildren without being as tired,’’ says Siler, whose children are 13, 9 and 7.

Her mother’s eyes tear up as she discusses what her daughter did for her and what it’s meant.

“I do feel that I’m really blessed,’’ Sinclair says. “I went back to visit at dialysis and I could see where I really had come from. I had come a long way, and it meant a lot.

“When I think about it now, it still fills me up,’’ she says, pausing to collect herself. “I realize I could be in that same position. I realize that if it hadn’t been for my family, I wouldn’t know what would have happened to me.’’

More Living Donors Needed

The best treatment for people with kidney disease is a live donor transplant, but Wake Forest Baptist researchers showed in a national study last year how difficult it can be for many African-Americans to obtain a transplant from a live donor.

Amber Reeves-Daniel, DO, a Wake Forest Baptist nephrologist who was principal author of the study, says the reasons behind the data are not clear.

She suspects there are several factors, including African-Americans waiting longer to be placed on waiting lists for living kidney transplant, as well as waiting longer to see physicians about their kidney problems to begin with.

In addition, although the data showed that all Medicaid recipients were less likely than those with other forms of insurance to receive a living donor transplant, African-American Medicaid recipients were much less likely to receive a living kidney transplant.

“I think it has a lot to do with economics and racial differences, but as you do research, all you find are more unanswered questions,’’ Reeves-Daniel says.

Siler says she believes there is an education factor involved in becoming a donor, and that many people, especially African-Americans, don’t understand the process and thus shy away from being living donors.

“It’s easy to say ‘no’ to what you don’t understand,” she says. “If I hadn’t gone out and done my own research, there would be have been critical key factors that I would have missed out on. If you have the knowledge, it’s makes your decision that much easier. I don’t think enough African-Americans see it as a possibility to live a long, normal healthy life after being a living donor.’’

Seeking a Longer-Term Solution

Participating in a research study at Wake Forest Baptist, Siler was tested to see if she was positive for the two variants in the APOL1 gene – before deciding whether to donate a kidney to her mother. She didn’t want to donate a kidney that could set her mother up for failure again. When that test proved negative, Siler told her surprised but elated mother what she was intended to do.

Siler says she hopes the research being conducted by Freedman and his Wake Forest colleagues can determine what triggers kidney disease for those with the two variants in their APOL1 gene.

Freedman says his team is looking at viruses in the urine that may protect from kidney disease, “kind of like a defense shield.’’

He believes that protective viruses may be absent in some people with APOL1 gene risk variants who develop kidney disease. Freedman says that studying interactions between viruses and genes could determine why some people with APOL1 risk variants develop kidney disease while others do not.

If that happens, he says, “I think we can hope for a rapid cure, or slowing of progression of kidney disease.’’

Having come through her own family kidney disease crisis, Siler says she prays the research pays off for her children and future generations.

“We’ve got to learn how to prevent kidney disease from reoccurring,’’ Siler says. “It’s very personal to me.’’

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